High incidence of lung cancer death after curative endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma

Abstract Background and Aim Following treatment of superficial esophageal squamous cell carcinoma (ESCC), surveillance for a second primary malignancy (SPM) is necessary. However, detailed evidence regarding the timing and prognosis of SPMs is insufficient. We aimed to clarify the details of SPMs and their effects on patient outcomes. Methods This retrospective, multicenter study involved 11 hospitals. Patients with superficial ESCC curatively resected using endoscopic submucosal dissection between May 2005 and December 2012, were included in this study. Results The 5‐year survival rate of 187 patients was 92.6% during a median follow‐up duration of 96.8 months. Thirty‐one patients died, 14 of whom died of SPMs. Compared to patients with SPMs detectable by esophagogastroduodenoscopy (EGD), patients with SPMs detectable only by modalities other than EGD had a significantly higher mortality rate (p < 0.001). Patients with second primary lung cancer (LC) had a high mortality rate (56.3%). Univariate and multivariate analyses showed that multiple Lugol‐voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91–6.50), and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08–11.41). Conclusions SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC. We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.


| INTRODUCTION
Esophageal cancer (EC) is the seventh most common cancer, and squamous cell carcinoma (SCC) is the most common histological subtype, accounting for 80% of all EC cases worldwide. 1EC is the sixth most common cause of cancer-related deaths. 1 If EC is detected and treated at an early stage, the outcomes may be favorable.][7][8][9] Even in cases where it invades the muscularis mucosa (MM), the risk of metastasis is relatively low (0-4.3%)with the absence of lymphovascular involvement and negative pathological margins. 8,10,11Therefore, considering the risk and invasiveness, the Esophageal Cancer Practice Guidelines (2022) 9 allow for the observation of such cases without additional treatments, such as chemoradiotherapy (CRT) or surgery, considering the risk and invasiveness.
Surveillance esophagogastroduodenoscopy (EGD) is necessary after ER for the early detection of metachronous ESCC. 4,9In addition, the ESD/EMR guidelines for EC in Japan 12 mention the need for surveillance of second primary malignancies (SPMs) in other organs.Previous studies have shown a high risk of other malignancies after ESCC treatment [13][14][15][16] and their effects on long-term outcomes. 7,17However, there is currently insufficient evidence to determine when other malignancies are detected or whether they are the cause of death in cases of curative ESCC resection.Therefore, this study aimed to clarify the details of SPMs, including their organs of origin or timing of detection, and how they affect patients' long-term outcomes after curative resection of superficial ESCC.

| Study design and patients
This multicenter retrospective study included 11 hospitals (one university hospital and 10 secondary or tertiary care hospitals; Table S1) that had participated in our previous study. 4From the databases and medical records of each institute, we identified and enrolled patients with esophageal neoplasia (ESCC or suspected ESCC) who had undergone ESD treatment between May 2005 and December 2012.The inclusion criteria for patients were as follows: (1) ESCC with a pathological depth of invasion up to the EP/LPM or MM, or high-grade intraepithelial neoplasia (HGIN), indicating lesions involving more than half of the epithelium; (2) no lymphovascular invasion;(3) negative horizontal and vertical margins; and (4) ESD was performed for the first time.9][20] The exclusion criterion was a history of treatment other than ESD, such as surgery or CRT, for EC.

| Clinical information
We retrospectively collected patient information, including background factors such as sex, age, history of had a significantly higher mortality rate (p < 0.001).Patients with second primary lung cancer (LC) had a high mortality rate (56.3%).Univariate and multivariate analyses showed that multiple Lugol-voiding lesions (LVLs) tended to be associated with SPMs (p = 0.077, hazard ratio [HR] 4.43, 95% confidence interval [CI]: 0.91-6.50),and metachronous ESCC was an independent risk factor for the incidence of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41).
Conclusions: SPMs that cannot be detected by EGD, such as LC, must be considered after the curative resection of ESCC.We suggest strict screening by both EGD and computed tomography for patients with multiple LVLs or metachronous ESCC to detect SPMs in their early stages.

K E Y W O R D S
endoscopic submucosal dissection, esophageal squamous cell cancer, lung cancer, second primary cancer other organ malignancies, alcohol consumption, and smoking, and endoscopic findings such as lesion size, location, macroscopic type, and pathological depth of invasion.The incidence of metachronous ESCC and SPMs and the long-term prognosis, especially in relation to SPMs, were investigated.SPMs were defined as malignancies diagnosed more than 2 months after the initial primary ESCC diagnosis in accordance with the SEER rules of the National Cancer Institute. 21It did not include metachronous ESCC.The decision whether to screen for other organ malignancies before ESD depended on each physician.

| Histological evaluation and follow-up
The specimens resected by ESD were fixed in 10% formalin and cut into 2-mm-thick slices.Histological assessment of the specimens was conducted according to the Japanese Classification of EC. 22 The size, histology, and invasion depth of the pathologically diagnosed specimens were analyzed.
The interval between post-ESD surveillance EGDs was determined by each physician based on the patient's background, such as age and comorbidities; however, follow-up EGD were typically conducted every 6-12 months.No specific guidelines were in place for performing computed tomography (CT) scans since the lesions were endoscopically diagnosed as superficial ESCC without submucosal invasion and histologically confirmed as curatively resected.Therefore, CT scans were performed approximately once a year, when each physician considered it necessary.

| Statistical analysis
Continuous variables are presented as median (range), while categorical variables are summarized as frequencies (percentages).Continuous variables were compared using the Wilcoxon test and categorical variables were compared using χ 2 or Fisher's exact tests.The development of metachronous ESCC and SPMs and survival were analyzed using the Kaplan-Meier method and the log-rank test.For some SPMs, we calculated the standardized incidence ratios (SIRs) using indirect standardization methods based on the Cancer Statistics of Japan (Cancer Statistics, Cancer Information Service, National Cancer Center, Japan [National Cancer Registry, Ministry of Health, Labor, and Welfare]). 14,23The data for 2020 and beyond were yet unpublished; therefore, we substituted them with those of 2019.The exact confidence intervals (CIs) around the SIR were calculated assuming a Poisson distribution of the observed number of neoplasms.We identified the factors related to SPMs using a Cox proportional hazards model with time-dependent covariates for univariate and multivariate analyses, estimating the hazard ratio (HR) and 95% CI.The adjustment was made for the SPMs and metachronous ESCC occurring after the first treatment for ESCC.Statistical significance was defined as p < 0.05.All analyses were conducted using EZR software (version 1.54, Saitama Medical Center, Jichi Medical University, Tochigi, Japan) on a personal computer.

| Ethics approval
The study protocol was approved by the Institutional Review Boards (IRB) of Osaka University (no.16352) and other participating institutions.The study was conducted in accordance with the principles of the Declaration of Helsinki.All participants were given the opportunity to decline participation in the study before the current investigation, utilizing the opt-out method made available on each hospital's website.An exemption of written informed consent was granted by the IRB for this purpose.

| Patients and lesions
During the study period, 312 patients underwent ESD for superficial esophageal neoplasia.Among them, a total of 187 patients who met the inclusion and exclusion criteria were enrolled in this study.The patient and lesion characteristics are shown in Table 1.Metachronous ESCC (25.7%) and SPMs (32.1%) developed during a median follow-up period of 96.8 months (range: 4.6-192.7 months) after curative resection of ESCC.

| Long-term outcomes and cause of death
Figure 1A shows the long-term outcomes of superficial ESCC resections.The 5-year survival rate was 92.6% and 31 deaths occurred.The details of the causes of death are shown in Figure 1B.Eighteen of the deaths (58.1%) were malignancy-related, and 14 of these (77.8%) occurred after ESCC treatment.There was only one case of ESCCinduced death, which was EP/LPM with metastasis to the lymph nodes and was treated with CRT.

| SPMs and their influences on the long-term outcome
SPMs were divided into two groups: those that can be detected using EGD, occurring from the oral cavity to the duodenum, and those that can be detected using only other modalities, mainly CT scan (Figure 2A).Patients with SPM that can be detected using a modality other than EGD had significantly higher mortality rates than patients with SPMs that can be detected using EGD (p < 0.001).Figure 2B illustrates the details of this process.The top three SPMs and their SIRs are as follows: 17.92 (95% CI: 13.91-21.92)for head and neck SCC (HNSCC), 2.83 (2.12-3.53)for lung cancer (LC), and 2.39 (1.77-3.01)for gastric cancer.Notably, patients with a second primary LC had a high mortality rate.Of the patients diagnosed with LC after ESCC resection, 56.3% died of LC.
Table 2 shows that the hazards to prognosis of SPMs, especially second primary LCs, were significantly high (p < 0.001, HR 6.57, 95% CI: 3.10-13.93and p < 0.001, HR 13.03, 95% CI: 6.13-27.67,respectively).We categorized the patients into two groups, those with and without SPMs, to compare their prognoses with the Kaplan-Meier curve (Figure S1A,B).Although they did not correspond to the results of the previous Cox proportional hazard model with time-dependent covariates, they showed worse prognoses of patients with SPM and second primary LC.

| Risk factors for SPMs and second primary LC after ESCC resection
Univariate and multivariate analyses were performed to explore risk factors for SPMs (Table 3).Univariate analysis revealed that it was associated with multiple Lugolvoiding lesions (LVLs) (p = 0.010) and metachronous ESCC (p = 0.035).Multivariate analysis was performed including these two factors and some factors that were considered to be associated with SPMs in patients with ESCC in previous studies. 15,16,24Multiple LVLs tended to T A B L E 1 (Continued) be associated with the SPM incidence after ESCC resection (p = 0.077, HR: 4.43, 95% CI: 0.91-6.50);however, no independent risk factor was revealed.
We also analyzed the risk factors for second primary LC, which were significantly associated with the outcomes (Table 4).Univariate analysis revealed that it was associated with metachronous ESCC (p = 0.014).As multiple LVLs tended to be associated with SPMs in this study, and smoking, age and sex have been reported as risk factors for LC 24,25 and are thought to be important factors, multivariate analysis was performed including these factors.As a result, metachronous ESCC was a significant risk factor of second primary LC (p = 0.037, HR 3.51, 95% CI: 1.08-11.41),and age > 69 years old tended to relate be associated with it (p = 0.055, HR 2.90, 95% CI: 0.98-8.60).

LC cases
Among the 16 patients with second primary LC, 81.3% (13/16) were smokers, and all nine patients who died due to LC were smokers (Table 5).Compared with the seven living patients with LC, nine dead patients were diagnosed after they had progressed to stages II-IV.The two patients who were initially diagnosed with stage I LC but died due to LC had developed metastatic recurrence after receiving LC treatment, then died because of it.Additionally, the interval between the chest CT scan when LC was initially detected and the prior CT scan during which LC failed to be detected was calculated as >1 year in 66.7% (6/9) of dead patients with LC and 16.7% (1/6) of live patients.
F I G U R E 1 (A) Long-term outcomes of patients with esophageal cancer after treatment and the details of the cause of death.The Kaplan-Meier curve shows the OS rate.(B) Causes of death in this study.† Malignancies diagnosed before ESCC treatment.ESCC, esophageal squamous cell carcinoma; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; LC, lung cancer; OS, overall survival; SPM, second primary malignancy.

Malignancies Others
In this study, we investigated the incidence of SPMs after curative treatment of superficial ESCC and the significantly poor prognosis of patients with SPMs.In addition, more than half of all deaths were due to malignancies, indicating the need for surveillance.As previously reported, the most commonly observed SPMs in patients with ESCC were HNSCC, LC, and gastric cancer, 14,15 and multiple LVLs were the important risk factor. 16To the best of our knowledge, this is the first study to show that SPMs, especially LC, which cannot be detected using EGD, have a Mortality rate and second primary malignancy stratified by the modality of detection.Patients whose SPM was detected using a modality other than EGD showed significantly higher mortality rates than those whose SPM was detected using EGD (p < 0.001).(B) Mortality rate and second primary malignancies.Although EGA is also an esophageal cancer, we considered it a distinct cancer from ESCC because it originates from gastric mucosa and has different risk factors.† Malignancies detected using EGD.EGA, esophagogastric adenocarcinoma; EGD, esophagogastroduodenoscopy; ESCC, esophageal squamous cell carcinoma; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; LC, lung cancer; SPM, second primary malignancy.

HR for mortality [95% CI] p Value
With strong impact on prognosis.Moreover, we found that occurring metachronous ESCC is the risk factor for second primary LC.
It is not surprising that SPMs that could not be detected by EGD were associated with a higher mortality rate.This is because no surveillance methods had been T A B L E 3 Univariate and multivariate analyses for second primary malignancies after ESCC resection.

Univariate analysis HR [95% CI]
p T A B L E 5 Details and their outcomes of second primary LC cases diagnosed after ESCC resection.Abbreviations: CT, computed tomography scan; ESCC, esophageal squamous cell carcinoma; ESD, endoscopic submucosal dissection; F, female; LC, lung cancer; M, male; SCC, squamous cell carcinoma.

Age
HNSCC or gastric cancer, were detected using EGD in this cohort, EGD surveillance for metachronous ESCC performed every 6-12 months enabled the early detection and treatment of these patients and improved their prognosis (Figure 2).Therefore, endoscopic surveillance would be appropriate not only for detecting metachronous ESCC but also for these cancers.In contrast, more than onethird of the malignancies that could not be detected using EGD were the cause of death, and more than half of the patients with LC died of LC, suggesting delayed detection.
Early-stage LC was more frequent in live patients than in dead patients.We should remember the risk factors for LC and actively screen the patients after ESCC treatment.
The present study showed that the development of metachronous ESCC was significantly associated with the incidence of second primary LC.Although smoking is a widely known risk factor for LC, [26][27][28] this study found no significant association between smoking and LC occurrence.One reason for this is the increased number of smokers (73.8%) among the study participants.However, more than 80% of patients with LC were smokers, and only two were nonsmokers.Among smokers, a second primary LC was more common in patients with metachronous ESCC (p = 0.012, HR 4.53, 95% CI: 1.39-14.72)(Figure S2).Therefore, LC should be increasingly considered when metachronous ESCC occurs in smokers.][31] A positive association between alcohol consumption and the risk of LC in smokers has been reported. 32Therefore, alcohol consumption may affect the incidence of LC in smokers.Other possible risk factors include the amount of smoking and alcohol consumption or continuous smoking or drinking after ESCC treatment.However, approximately 30% of information on these factors was missing in this retrospective study (Table S2); therefore, we could not analyze them.Considering the present results, we believe that regular chest screening is advisable during follow-up for patients with metachronous ESCC, recognizing that they are at a high risk of developing a second primary LC.
Low-dose CT scans, which can reportedly reduce LC mortality, 33 are suitable for LC screening.Regarding chest screening before ESD, 77.5% (145/187) of the patients underwent a chest CT scan before ESD (Table 1).In addition, all the patients who had not undergone a CT scan underwent chest radiography, except five patients.All LC death patients in this study had a chest CT scan prior to ESD, but the follow-up CT scan interval for approximately half of the cases exceeded >1 year.In contrast, many of the live patients with LC underwent CT scans every 6-12 months.Thus, we believe that high-risk patients, such as smokers or/and those with metachronous ESCC during the follow-up period, should undergo CT scans at least once a year or stricter screening is warranted.
This study had several limitations due to its retrospective nature.First, there was selection bias.As this was a multicenter study, bias was reduced.Second, some patients had a short follow-up duration.The median follow-up time was 96.8 months, and 77% of all patients were followed up for longer than 5 years; therefore, the observation period was considered sufficient in many cases.Third, surveillance methods, such as modalities or intervals, were not standardized.Future studies are needed to determine appropriate surveillance methods and timeframes.Finally, there was a lack of data on smoking and drinking statuses.Further prospective studies with a larger number of cases, longer follow-up periods, and fewer missing values are warranted.
In conclusion, after curative resection of superficial ESCC, it is important to be aware of the risk of SPMs, especially those that cannot be detected using EGD, such as LC.Metachronous ESCC was significantly related to second primary LC.We suggest strict screening not only via EGD but also via CT scan for patients with such risk factors to detect SPMs, including LC, in their early stages.

2
Association between SPM or second primary LC and their prognoses.
Patient and lesion characteristics.
T A B L E 1 Univariate and multivariate analyses for second primary LC after ESCC resection.
Abbreviations: CI, confidence interval; EP, epithelium; ESCC, esophageal squamous cell carcinoma; HGIN, high-grade intraepithelial neoplasia; HR, hazard ratio; LPM, lamina propria; LVL, Lugol-voiding lesion; MM, muscularis mucosa.establishedbasedon any modality other than EGD after ESD.On the other hand, the malignancies that were detected by EGD could generally be detected in the early stage if EGD was appropriately performed and could be treated by minimally invasive treatment.The present study shows the extent by which the mortality rate differs between malignancies that can or cannot be detected by EGD after ESCC treatment.Although many SPMs, such asT A B L E 4Abbreviations: CI, confidence interval; EP, epithelium; ESCC, esophageal squamous cell carcinoma; HGIN, high-grade intraepithelial neoplasia; HR, hazard ratio; LC, lung cancer; LPM, lamina propria; LVL, Lugol-voiding lesion; MM, muscularis mucosa.